The cranial neural crest (CNC) cells are stem/progenitor cells that contribute to the vertebrate craniofacial structures and cardiac tissues One of the earliest and most critical stages in CNC development is the specification of the CNC, which requires induction of the transcription factor Snail2, a process that is also used by carcinoma cells to trigger their invasion. Therefore, understanding the basic mechanisms for CNC specification is critical for developing new methodologies for the prevention and treatment of CNC-related birth defects and carcinoma invasion. The goal of the current application is to elucidate the molecular pathways through which ADAMs 13 and 19, two disintegrin metalloproteinases (ADAMs), function in CNC specification. The application has three specific aims. The first aim is to define the roles of ADAM13 in regulating canonical Wnt signaling. The hypothesis to be tested is that ADAM13 cleaves and inactivates two ephrin-Bs, which function as novel antagonists of canonical Wnt signaling, a major signaling pathway that is essential for CNC specification. The second aim is to determine the mechanism of action for ADAM19 in CNC specification, and the focus will be on the functional interaction between ADAMs 13 and 19. In the third aim, both candidate and genomic approaches will be used to identify the downstream transcriptional targets of the ADAM-ephrin-Wnt signaling axis. Outcomes of this proposed research should provide new insight into the interactions of ADAM proteases, ephrin-Bs and Wnt signaling, three important regulatory elements in CNC development and carcinoma invasion. Based on this information, new methods may be developed to induce CNC cells for therapeutic purposes or inhibit carcinoma invasion.